Substituted benzamides as modulators of trex1

Abstract

Provided are compounds of Formula (I): (I) and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with TREX1.

1 . A compound having the Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is halo, hydroxy, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or halo(C 1 -C 4 )alkoxy; 
 R 2  is hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylOR a , —C(O)R b , —C(O)OR b , —C(O)NR b R c , —C(O)NR b R c , 5- to 7-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein said heteroaryl and heterocyclyl are each optionally substituted with 1 to 3 groups selected from R 6 ; 
 R 3  is halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, —NR b R c , or CN; 
 R 4  is halo, hydroxy, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, CN, —NR b R c , —C(O)R b , —C(O)OR b , —C(O)NR b R c , —SR b , —C(O)NR b R c , —S(O) 2 R b , —S(O)R b , —NR b C(O)R c , —NR b C(O)OR c , —NR b C(S)OR c , and —NR b C(O)N c R d ; 
 Ring A is nitrogen-containing 5- to 7-membered heteroaryl; 
 R 5  is halo, hydroxy, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, oxo, —(C 1 -C 4 )alkylOR d , —(C 1 -C 4 )alkylC(O)R d , —(C 1 -C 4 )alkylC(O)OR e , —(C 1 -C 4 )alkylC(O)NR d R e , —C(O)R d , —C(O)OR d , —C(O)NR d R e , —C(O)NR d SO 2 (C 1 -C 4 )alkyl, CN, —NR d R e , —C(O)NR d SO 3 H, —NR d C(O)R d , —NR d C(O)OR e , —NR d C(S)OR d , —NR d C(O)N e R f , —NR d C(S)NR e R f , —N d S(O) 2 NR e R f , —C(S)R d , —S(O) 2 R d , —S(O)R d , —C(S)OR d , —C(S)NR d R e , —NR d C(S)R e , —SR d , —(C 1 -C 4 )alkylC(O)NR d R e , —(C 1 -C 4 )alkylC(O)NR d SO 2 (C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylNR d R e , —(C 1 -C 4 )alkylC(O)NR d SO 3 H, —(C 1 -C 4 )alkylNR d C(O)R e , —(C 1 -C 4 )alkylNR d C(O)OR e , —(C 1 -C 4 )alkylNR d C(S)OR e , —(C 1 -C 4 )alkylNR d C(O)N e R f , —(C 1 -C 4 )alkylNR d C(S)NR e R f , —(C 1 -C 4 )alkylNR d S(O) 2 NR e R f , —(C 1 -C 4 )alkylC(S)R d , —(C 1 -C 4 )alkylS(O) 2 R d , —(C 1 -C 4 )alkylS(O)R d , —(C 1 -C 4 )alkylC(S)OR d , —(C 1 -C 4 )alkylC(S)NR d R e , —(C 1 -C 4 )alkylNRd b C(S)R c , —(C 1 -C 4 )alkylSR d , 5- to 7-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein said heteroaryl and heterocyclyl are each optionally substituted with 1 to 3 groups selected from R 7 ; 
 R a , R b , R c , R d , R e , and R f  are each independently hydrogen, (C 1 -C 4 )alkyl, or halo(C 1 -C 4 )alkyl; 
 R 6  and R 7  are each independently halo, hydroxy, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, CN, or oxo; 
 m and n are each independently 0, 1, 2 or 3; and 
 p is 0 or 1. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein
 R 2  is hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylOR a , 5- to 7-membered heteroaryl, or 4- to 7-membered heterocyclyl, wherein said heteroaryl and heterocyclyl are each optionally substituted with 1 to 3 groups selected from R 6 ;   R 3  is halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, or CN; and   m and n are each independently 0, 1, or 2.   
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is halo, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or halo(C 1 -C 4 )alkoxy. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein the compound is of the Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen or (C 1 -C 4 )alkyl. 
     
     
         9 . The compound of  claim 1 , wherein the compound is of the Formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, or halo(C 1 -C 4 )alkoxy or CN. 
     
     
         11 - 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2. 
     
     
         15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein the compound is of the Formula IV: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyrazolyl. 
     
     
         18 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl. 
     
     
         19 . The compound of  claim 1 , wherein the compound is of the Formula V: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 1 , wherein R 5  is in the para position with respect to the connection point for ring A. 
     
     
         21 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is halo, oxo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, —C(O)OR b , —NR b R c , —C(O)NR b R c , —(C 1 -C 4 )alkylOR b , —(C 1 -C 4 )alkylC(O)R b , —(C 1 -C 4 )alkylC(O)NR b R c , —C(O)NR b SO2(C 1 -C 4 )alkyl, 5- to 6-membered heteroaryl, wherein said heteroaryl is optionally substituted with 1 to 3 groups selected from R 7 . 
     
     
         22 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is oxo, CF 3 , CH 3 , C(O)OCH 3 , C(O)OH, CH 2 COOH, NH 2 , CONH 2 , CH 2 CONH 2 , CONHCH 3 , CH 2 OH, CH 2 CH 2 OH, CONHSO 2 CH 3 , tetrazolyl, pyrazolyl, triazolyl, or pyrazolyl, wherein said pyrazolyl is optionally substituted with hydroxy. 
     
     
         23 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2. 
     
     
         24 . (canceled) 
     
     
         25 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         26 . A method of treating a disease responsive to the inhibition of TREX1 in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method of  claim 26 , wherein the disease is cancer. 
     
     
         28 - 55 . (canceled) 
     
     
         56 . The compound of  claim 1 , wherein the compound is selected from any one of the following or a pharmaceutically acceptable salt thereof: